Thursday, March 31, 2011

In my 30 years in charge of a blood bank we only twice gave a patient the wrong blood. The first occasion was when the othopedic ward was closed for August. A patient was returning to the general surgical ward having had a hip replacement. A ward sister instructed a staff nurse to set up a unit of blood for him. Unfortunately, a general surgical patient returned from the OR at the same time and the nurse gave the first patient blood meant for the second one. She did not follow protocol and never checked with another nurse that she was giving the correct blood. It was in fact group A blood into a group O patient. He had a massive transfusion reaction with acute kidney failure, but he recovered completely after three weeks in intensive care. He sued the hospital for £5000. He was badly advised - he could easily have got £50,000.

The second occasion was caused by a lab technician who just picked up the wrong tube of blood to cross match and didn't read the label. Luckily he realized his mistake and rushed over to the ward and stopped the transfusion when only 10cc had gone in. The patient suffered no ill effects and he did not sue the hospital.

Here's the amazing thing. It was the same patient, in this time for a prostate operation. When I told my colleague he snapped his fingers and exclaimed, "Bother! But we will get him next time!"

The patient could be excused if he thought that there was a conspiracy out to get him. Who would be responsible? MI5? The CIA? The IRA?

I have just been reading Voodoo Histories by David Aaronovitch, a book about conspiracy theories. It covers the Protocols of Zion, supposedly a conspiracy among rich Jews to take over the world, the show trials in Russia, supposedly uncovering a conspiracy among Trotskyites and particularly among Trotskyite Jews to sabotage Stalin's five-year plans, the America-Firsters who suspected a conspiracy to get America into the second world war for the benefit of Roosevelt's (mostly Jewish) friends in the armaments and banking industries who would make a killing from war profiteering (viz Steinbeck's East of Eden). It was even suggested that Roosevelt engineered the Japanese attack on Pearl Harbor to ease America's way into the war. It goes on to cover the McCarthy hearings, aimed at detecting a plot by Jewish movie moguls at indoctrinating America's youth with communistic ideas.

You may have guessed by now that Aaronovitch is Jewish and is particularly sensitive to conspiracies implicating Jews, but this should not detract you this book deals with other issues and is pretty comprehensive and well written.

Of course the Kennedy killings were ripe for the conspiracy theorists. Oliver Stone's film JFK would have made the apparent inconsistencies of the Warren report available to a wide audience. It seems to me that Lee Harvey Oswald, acting alone, was a nutter who wanted to be famous and Jack Ruby was an angry anti-communist who wanted revenge. Similarly, Sirhan Sirhan shot Robert Kennedy and Ted Kennedy was alone responsible for Chappaquiddick. Marilyn Monroe was not murdered at the behest of RFK, Martin Luther King was not murdered as an FBI or CIA conspiracy, the Bush cabal did not blow up the levies in New Orleans to kill black people, OJ Simpson probably did kill his wife, Princess Diana should have been wearing a seat-belt and she might have survived the accident in Paris, David Kelly, the weapons inspector committed suicide and was not murdered by MI5 at the behest of Tony Blair. There was no Passover plot not has the Catholic church kept secret that the descendants of Jesus and Mary Magdalene living in France.

The question is why are such conspiracies so easily believed in. It is interesting that many will dismiss many obviously ridiculous conspiracy theories but then say I am sure we are not being told the truth about --- it could be anything. Very intelligent people dabble in areas in which they are not expert, but have heard it from a trusted source. Since the Internet became available these theories have 'gone viral' as they say. They have been widely believed in however implausible. There has come a new definition of truth. No longer is there objective truth, merely a truth that fits my prejudices. They call it post-modernism.

We all like a story. The truth is that real life isn't a story. Like my anecdote about blood transfusions, co-incidences happen. Life stories don't have a beginning, a middle and an end. They don't resolve themselves with a happy ending or even a sad one. They just sort of dribble out. Perhaps our minds are conditioned to look for patterns in everything we see. I once attended a lecture by epidemiologist, Ray Carwright, during which he plotted on a map cases of childhood leukemia. He told us that every one of these was within 5 miles of a military establishment. Of course, we all expected this to be something to do with radiation, but at the end of the lecture he told us that the military establishments were iron-age hill forts.

Far more dangerous than the conspiracy theories is the reaction to them by those who believe in them. After all, Hitler believed in the protocols of Zion and these are still believed in by most Arabs. Similarly, street Arabs are absolutely convinced that 9/11 was the result of a plot between George W Bush and Mossad.

Of course we who believe in absolute truth can dismiss these theories with aplomb.

Today is the 200th anniversary of Robert Bunsen, inventor of the famous Bunsen Burner, with which every school lab is equipped with dozens. He is featured in today's Guardian. His reason for wanting a steady hot flame was to study the spectral properties of elements; the characteristic, brightly coloured light emitted by different elements when they are heated. He went on to split this light into its constituent wavelengths using a prism, in the process inventing a prototype of today's spectroscopes and founding the brand new scientific field of spectroscopy. They discovered that every element emits a distinctive mix of wavelengths that can be used like a fingerprint to identify its presence.

The same trick is used by astronomers to examine stars millions of light years away and say exactly what they're made of. Thousands of chemistry students will have sprayed a solution of sodium chloride in a flame to recognise the characteristic orange color. I remember starting out as a pathology doctor measuring sodium and potassium levels using a moving wire flame photometer. Every window in the building had to be closed lest a stray wind blew out the flame.

Bunsen detected a previously unseen blue spectral line produced by mineral water which he guessed was being emitted by an unknown element. Having gone to the extraordinary length of distilling 40 tonnes of water to isolate 17 grams of the new element, he called it caesium, meaning "deep blue" in Latin.

He also discovered that adding iron oxide hydrate to a solution in which arsenic was dissolved would precipitate the poison and render it harmless. To this day, the compound is used as an antidote for arsenic poisoning.

America is the most Christian nation on the planet. But in American movies the watchword is not "Salvation" but "Freedom".

The nation began by seeking freedom from Great Britain. Its greatest war was about freeing the slaves, though the other side painted it as freedom from the hegemony of the Northern states. The isolationist movement in the 1930s talked about the freedom from being involved in foreign wars. The Second World War has been recorded as a war to free the Jews, though the Japanese were not anti-Semites and the Pacific war was by far the bitterest conflict for Americans. The cold war was about freedom from communism and today many in America want freedom from big government.

Here in Galatians chapter 5 we learn that it is for freedom that Christ has set us free! We are warned not to slip back into slavery. Christ died once and for all to set us free from the Law. Of course, as Gentiles you were never under the law, but this was not an advantage to you. You were still sinners, ignorant sinners, but sinners none the less. The advantage the Jews had was that they knew they were sinners in every detail. But their only remedy was an endless series of animal sacrifices that were only a picture of the real thing. They were waiting for absolution which would only come from the suffering servant of Isaiah 53. By his stripes we are healed, was the promise. The Lord has laid on him the iniquity of us all.

You can't have both! Either you are trusting Christ or you are trusting your own behavior for salvation. And if you go back to trusting in the Law, then Christ is worthless to you. I don't mean that you should go around being wicked so that grace might abound. By no means; we are to be imitators of Christ in doing good works, but it is why we are doing good works. Listen to Chris Kelly's illustration: If I fail to buy my wife flowers on her birthday I'm in the doghouse. The following year I remember to buy her flowers and I present her with them saying 'Last year I was in the doghouse for months because I forgot, so I've remembered this year because I don't want the same again. But I get the same again. The following year I say to her I've been reading a book about how to keep your marriage sweet so I've bought you two bunches of flowers. Doghouse again. Finally he says, "I've bought you these flowers because I love you." Success!

We imitate Christ because we love him.

The only thing that counts is faith expressing itself through love (v5).

Paul comes down hard on those who are trying to seduce the Galatian Christians (v12). James tells us that not many should presume to become teachers (James 3:1) because those who teach will be judged more strictly. Even a small suggestion of heresy is very dangerous - a little yeast works through the whole batch of dough (v9).

Paul was continually persecuted because of the scandal of the cross (v11). It is a truism to say that Christians are always tempted to water down the message. "It's too bloody this gospel - Mel Gibson's film went over the top with all that blood. We should concentrate of Jesus’ life and example not on some conjuring trick with bones. There were a lot of stories going around at the time; we should take Temple curtains torn in two and graves giving up their dead with a pinch of salt. He was not really killed; he was drugged on the cross and woke up later in the cool of the tomb and went off and married Mary Magdalene. They escaped form Jerusalem and he went on to father future kings of France."

Today the story of the cross is just as offensive to most people - a stumbling block to Jews and foolishness to Gentiles, but to those whom God has called, both Jews and Greeks, Christ the power of God and the wisdom of God.

He came as a witness to testify concerning that light, so that through him all men might believe.

The word witness is the same word that we get our word martyr from and indeed John the Baptist would later be martyred. What a brave man he must have been. He was able, by God's grace to stand up to the wicked and absolute ruler and accuse him to his face of adultery. Because of his ascetism many see John as a hard man, but it was the quality of his personal life that made Herod sit up and take notice of him.

Notice that God's purpose in sending John was so that all men might believe. There is no sense in which John was only preaching to the elect. The gift of the Gospel is open to all sinners, whether they be Muslims, Buddhists, Hindus or atheists; whether they be hypocrites or adulterers, homosexuals or drug addicts, murderers or rapists.

Wednesday, March 30, 2011

This was John the big dipper. He was baptizing in the Jordan where there was much water.

King James, when he commissioned the 1611 translation insisted that the Greek should just be transliterated rather than translated as the Puritans wanted. They would have preferred dipped or immersed, but the Puritans had the last laugh as many of them were called Baptists thereafter.

Notice that it wasn't John's idea. He was sent by God. 'John' means 'Jehovah has been gracious' and so he had.

Tuesday, March 29, 2011

The light shines in the darkness, but the darkness has not understood it.

What is this darkness? Was not the creation the work of God's hand? How can it be anything other than good? Because of the Fall. Darkness here represents the evil in the world because of Adam's disobedience. The Fall caused the world to be cursed. Every bit of selfishness, greed, hate, spite and wickedness stems from the Fall. That is the darkness that the light shines on. Light not only reveals what is in the dark corners, it banishes darkness and this is light so bright that there are no shadows remaining.

The word translated understood is a difficult translation. Other versions have 'comprehend', 'apprehend', 'appropriate', 'overcome', 'put it out', 'extinguish', 'perceive', 'stop' or 'absorb',. The root of the word means 'to grasp hold of'. We are told by the experts that this is also a figure of speech called litotes, which means to undersell for effect. The best known example in British English would be "It ain't 'alf 'ot, mum." the plaintive cry of the British soldier in India or North Africa, meaning it is very hot indeed.

My own best shot at the meaning would be 'doesn't get anywhere near getting hold of it' which carries the double meaning of understanding and defeating. The light is victorious, nay, triumphantly victorious! Overwhelmingly victorious!

Monday, March 28, 2011

Paul continues his arguement contrasting the Law and grace by referring to the story of Abraham and the slave girl.

God had promised that Abraham was to be the father of many nations but his wife was old beyond the age of child bearing. What was a man to do? Put her away and find himself a younger model? That's what rich and powerful men do today. They call them trophy wives. Sarah seems to have been content to remain his wife, but let him take a slave girl for child bearing purposes. So Ishmael was born. A child born in a natural way, but as a child of a slave, still a slave.

Why is it that men behave in this way? King David was the same, so were Jacob and Judah. They never seem to take promises seriously. But God does. Let me take you back to the strange happening recalled in Genesis chapter 15. God had made a promise to Abraham who demanded a sign that God was serious. God had him bring a heifer, a goat, a ram, a dove and a pigeon. They were prepared and arranged opposite each other and when night fell a torch and a brazier appeared and passed between the pieces of the animals. I don't understand how this was significant, but it was certainly miraculous and was meant as a sign that God had truly made a covenant with Abraham. But Abraham didn't trust God enough to keep his promise and sired Ishmael on a slave woman.

In God's time he performed a miracle and Sarah bore Abraham a son in her old age. Isaac was a miracle baby; a son of the promise.

Paul in Galatians chapter 4 verse 24 tells us that these things may be taken figuratively, for the two women represent the two covenants. Hagar, the slave woman represents slavery under the Law, but Sarah represents freedom. And he quotes Isaiah 54:1, a prophesy of the barren woman bearing children.

If you are a slave then your future depends on your performance and if you fail to perform you can be thrown out, just as Hagar was thrown out when she began persecuting Sarah. If you are under the Law you had better perform or your future will be the same. And we know that no-one can keep the Law perfectly. James tells us that whoever keeps the whole law and yet stumbles at just one point is guilty of breaking all of it (James 2:10).

On the other hand Isaac was the son born of promise and by the power of the Spirit. We are, exclaims Paul, not children of the slave woman, but children of the free woman. We are not children of God because we obey the instruction but because of God's free grace. If it were our performance that determined our salvation we could never be secure; instead it is God's love freely given. Not because we were better than others or because we deserve it more. God loves us because he loves us. There is nothing that can separate us from the love of God. Not life nor death. Not angels nor demons. Not the present nor the future nor any powers. Not height nor depth nor anything else in the whole creation!

My first impression when I read this verse was to think of dead bodies. It is true that when you see a corpse you are aware that the light has gone out of the eyes, but this is not what is meant here. Always (54 times) in John's writings 'life' means spiritual life. When he tells us that 'he who believes in me shall never die' he means 'die spiritually' since even Lazarus had to die again. The 'everlasting life' of John 3:16 is not physical life but spiritual life. We will all be raised on the last day, but our lives on Planet Earth will end unless the Lord first returns. All physical life does come from the Word as verse 3 tells us, but this verse deals with a different type of life. This type of life is the source of Man's illumination. It is this light from which darkness flees; this light that shines in every dark corner; this light that is the negation of everything evil.

Sunday, March 27, 2011

The explosions and radiation spills at the Fukushima Daiichi power station in Japan may give an unfair impression of the risks associated with modern nuclear energy generation. The Fukushima reactors are a 40-year-old design. A new generation of reactors, with more comprehensive safety features and power backups, would likely have fared much better. Alexis Marincic, chief technical officer of French reactor-maker Areva, claims that most of the failures that led to Fukushima's radiation leaks would probably not have happened with the latest designs.

Problems began at Fukushima when it lost electrical power to its reactor cooling systems after the earthquake damaged power lines to the plant and the tsunami engulfed its backup diesel generators. Areva's European Pressurised Reactor (EPR) has six backup diesel generators in two seismically damped, waterproof concrete buildings sited 50 metres either side of the containment. “Even if an aircraft crashes into the reactor building we will still have backup power for cooling,” says Marincic. The EPR also has four separate backup circuits for the electronics, pumps, valves and pipework that keep the core cool in an emergency.

Lacking cooling, some reactors at Fukushima overheated, splitting water molecules to produce hydrogen, which then ignited. This blew the roofs off the containment buildings and released steam contaminated with radioactive isotopes. To avoid this, the EPR has a catalytic hydrogen recombiner that ensures any hydrogen generated reacts with oxygen to reform water. The reactor is kept in a double-walled, leakproof containment to stop gases escaping. An inner steel-lined prestressed concrete shell 0.8 metres thick is surrounded by a 1-metre-thick reinforced concrete shell.

We still don't know if there was a core meltdown at Fukushima but the EPR guards against this too, says Marincic. The design includes a water-cooled concrete “core catcher” that stops a melting core from exploding. Two EPRs are now being built, one in Finland and one in France. Areva's rival, Westinghouse Electric, owned by Toshiba of Japan, is building a third-generation reactor of its own, the AP1000, at a site in China. Like the EPR, it has stronger doubled-up containment and multiple cooling system backups. It also has a passive safety feature: an enormous tank of water in the roof that is automatically released in the event of a cooling system loss. Effectively, this would do what the Fukushima workers did with pumped seawater, says John Gittus, former safety director at the UK Atomic Energy Authority, but without requiring pumps. “A flap opens and out it pours,” he says. “We've calculated that a tank of water that can flood the pit that the reactor sits in can cool it for 72 hours, giving operators a good three days to work out how to deal with the situation,” says Westinghouse spokesman Adrian Bull.

Both reactor designs impress Andrew Sherry, director of the Dalton Nuclear Institute at the University of Manchester, UK. “These new reactors would have managed the core residual decay heat in a Fukushima situation – and once you have managed that your reactor would be in a safe shutdown mode.” Complex safety systems won't come cheap. “But cost is not such an issue,” says Gittus. “Regulators won't let people buy reactors that might go wrong.”

We tend to trust the Japanese as efficient engineers, but their 'shame' culture leads them to cover-up their mistakes rather than admit them. Consider the failings of their nuclear industry:

December 1995 Coolant leaks from a pipe at the Monju fast-breeder reactor. Managers supply a doctored video excluding the worst of the spill.

March 1997 Fires and an explosion hit the Tokaimura waste reprocessing facility. Radiation levels are found to be at least 10 times as high as initially reported. Seven maintenance staff are later found to have been out playing golf.

September 1999 In what is billed as the worst nuclear accident since Chernobyl, three workers at Tokaimura inadvertently create a critical mass of uranium, triggering chain reactions. Two workers eventually die; six managers are arrested and charged with professional negligence.

September 2002 Newly revealed reports from the International Atomic Energy Agency, dating from the 1990s, describe safety precautions at Japanese reactors as dangerously weak, with 90 deficiencies in safety procedures. Four companies – TEPCO, Chubu Electric Power, Japan Atomic Power and Tohoku Electric Power – admit they have hidden flaws from regulators.

August 2004 A steam leak from a power turbine at the Mihama plant kills four people and injures seven. The Kansai Electric Power Company is criticised for not inspecting the failed pipe.

March 2006 A diplomatic cable from the US embassy in Tokyo, later released by WikiLeaks, discusses a case in which a court orders the Hokuriku Electric Power Company to shut down a reactor at its Shika nuclear plant because of concerns over its ability to withstand powerful earthquakes. Both the company and the Japanese government oppose the ruling.

July 2007 Three reactors at the world's largest nuclear plant, Kashiwazaki-Kariwa, shut down after a 6.8-magnitude quake. TEPCO initially says that the quake caused no radiation leaks, but days later admits that 1200 litres of radioactive water have washed into the sea.

In 1975, about 30 dams in central China failed in short succession due to severe flooding, an estimated 230,000 people died. Include the toll from this single event, and fatalities from hydropower far exceed the number of deaths from all other energy sources. In contrast, the International Atomic Energy Agency and the UN estimate that the death toll from cancer following the 1986 meltdown at Chernobyl will reach around 9000. In fact, the numbers show that catastrophic events are not the leading cause of deaths associated with nuclear power. More than half of all deaths stem from uranium mining, says the IEA. But even when this is included, the overall toll remains significantly lower than for all other fuel sources.

“There is no question,” says Joseph Romm, an energy expert at the Center for American Progress in Washington DC. “Nothing is worse than fossil fuels for killing people.” Fine particles from coal power plants kill an estimated 13,200 people each year in the US alone, according to the Boston-based Clean Air Task Force. From coal we have a steady progression of deaths year after year that are invisible to us, things like heart attacks, whereas a large-scale nuclear release is a catastrophic event that we are scared about.

Through him all things were made; without him nothing was made that has been made.

Jesus the creator. He wasn't just the apprentice; God the Father letting him try his hand at a few minor beetles. Jesus created all things. Nothing was left for any other. We tend to make Jesus subsidiary to God the Father, but we fall down in our idea of the Trinity when we do so. There is but one God. I don't understand how there can be three persons and one God, but when we start separating them into three Gods or see each person as merely an aspect or face of God then we fall short. God made everything but the 'word' made everything; nothing was made without him.

Saturday, March 26, 2011

Cricket on the Indian sub-continent is a different game. The four semi-finalists in the World Cup comprise three teams used to the local conditions (India, Pakistan and Sri Lanka) and New Zealand who are not and did very well to defeat pre-tournament favorites, South Africa. Different types of cricketers are required for Indian conditions. Tall fast bowlers are a liability on these slow pitches and the atmosphere is generally too dry for swing bowlers. Slow bowlers are best suited to the conditions, but even they have to be unorthodox. Variation of pace and flight are essential, especially in the shortened form of the game.

One wonders how the great spinners of the past would have performed. Last week saw the death of Fred Titmus at the age of 81. He played for Middlesex from the age of 17 until nearly 50. He was a grammar school boy who was a self made cricketer. Only five first-class cricketers have scored 20,000 runs and taken 2,500 wickets: Rhodes and Hirst of Yorkshire, Tate of Sussex, WG Grace and Fred Titmus. He was in good company. He did the classic double of 1,000 runs and 100 wickets in a season eight times, a figure bettered by only four men, and his 2,830 wickets place him in the all-time top 10 of bowlers. Sixteen times he took 100 wickets, with a best of 191 in 1955, when he also scored his maiden century and topped 1,000 runs for the first time.

On a tour of the Caribbean in 1967-68, when on a boat trip out of Barbados's Sandy Lane Bay his left foot got caught in the propeller and he suffered the loss of four toes. His fellow tourists thought he might never play again, but two months later he was bowling for Middlesex, on his way to another haul of 100 wickets.

His last appearance was in late August 1982, nearing his 50th birthday. He popped into the pavillion at Lords and the Middlesex captain, Mike Brearley, playing his last game at Lords recruited him as a third spinner for a turning pitch. He took three vital wickets on the last afternoon and Middlesex clinched victory. On his second appearance for the county he had played alongside Brearley's father, Horace, who was making his last appearance.

The personal pronoun tells us that the 'word' is a person not a personification. He was with God and he was God. And he was there at the beginning. We can have no truck with the JW's notion that Jesus was a created being. At the very start we have here evidence of the plurality of personage in God. I don't understand the Trinity. I could not explain it. But then if I could I would be like God. There are mysteries in the Bible that we will only understand in heaven. Sometimes we just have to say, "I don't understand, but I believe."

Friday, March 25, 2011

In the beginning was the word and the word was with God and the word was God.

Every Jew would recognize the first words of the Torah, "In the beginning..." but the Genesis story begins with chaos coming to order. John tells us that there was order at the beginning. The 'word' or 'logos' is a strange term to describe what was there at the beginning. Only John uses it in the whole Bible (in his gospel, his first letter and in Revelation). But it tells us something about God. He is order not chaos; he is creative not destructive; he is intelligent; he is plural. Once something is something it is not nothing. By naming it everything else is excluded. A cat is not a dog; a book is not a table; a God is not a devil.

Logos implies more than just speech. In Proverbs chapter 8 this description is given of 'wisdom': I was there when he set the heavens in place, when he marked out the horizon on the face of the deep, when he established the clouds above and fixed securely the fountains of the deep, when he gave the sea its boundary so that the waters would not overstep his command, and when he marked out the foundations of the earth. Then I was the craftsman at his side. I was filled with delight day after day rejoicing always in his presence.

But we are talking about more than the personification of an attribute of God. We are talking about a real person. The word was both with God and actually God. From the first God was one but he was also more than one. This paradox will unfold as we read on.

Thursday, March 24, 2011

Have you ever had the impression that something has gone badly wrong in your spiritual life? There was once a time when it was your commonplace habit to talk about Jesus Christ every day, when reading your Bible was such a joy that all these reading schemes that talk about 4 chapters a day, or getting through the OT once and the NT twice in a single year seemed impossibly restricting, when you were at every meeting even some that were not really meant for you. There was a time when prayer was virtually continuous.

But now, it is somehow empty. The services always seem to annoy you; some glitch with the amplifier, a sour note on the trumpet, that wretched synthesizer again (why can't they use the organ?), your favorite seat taken by a visitor, a grammatical mistake by the preacher, you don't like the way they insist on breaking up into small groups to pray, the sermon is too long, the pews too hard, the hymns don't fit the music, the flowers are tired, someone else is serving communion, there always seems to be something that spoils it for you. And why have they switched versions of the Bible? OK the KJV was archaic but we were familiar with it and the cadence of the prose was magnificent. The gender non-specific NIV is too PC. The ESV may be correct in its translation but it doesn't flow like the NIV. Why is it that the passage for the day always seems to be an endless string of 'begats' or a story about some brutal Iron Age despot slaughtering his enemies down to the last woman and child? And what is the point of prayer? It's just talking to the ceiling, trying to make you feel better. If God wants to do something different he'll do it without advice from me.

Have you been there? What is the remedy? You had better start going to the evening service instead of just the morning. You had better reinstate your Bible reading plan. Are you tithing? Have you let that slip too? Better check with your bank balance. Trouble with prayer? Form a prayer triplet to help you.

Stop! Those may all be good things to do, but none of them is the remedy. Actually there is nothing you can do to restore your spiritual life. What do you mean Dr Hamblin? Are you implying that I am not just backslidden but actually an apostate? Am I the man of Hebrews 6? It is impossible for those who have once been enlightened, who have tasted the heavenly gift, who have shared in the Holy Spirit, who have tasted the goodness of the word of God and the powers of the coming age, if they fall away, to be brought back to repentance, because to their loss they are crucifying the Son of God all over again and subjecting him to public disgrace.

By no means. What I am saying is that you are powerless to restore your spiritual health. Think back to what you did to convert yourself? Nothing, it was all of Christ. What did you do to sanctify yourself? Again, nothing. It was the work of the Holy Spirit. So why do you think you can restore your spiritual health?

There is only one thing able to restore you and that is the Gospel. Read about Jesus. Preach the Gospel to yourself. Listen to Gospel sermons. Concentrate on Jesus. This is the Gospel. God loves you. He loves you so much that he gave his one and only son for you. Jesus loves you. He loves you so much that he laid down his life for you. He suffered agony instead of you so that your sins would not be punished. And not just physical agony. He who had been one with the Father from eternity past and will be until eternity future had that bond of love wrenched apart, suffering separation from God the Father so that you would not have to. The Holy Spirit loves you. He loves you so much that his every minute is spent watching over you, guiding you, guarding you, leading you to Jesus.

And your part in all this? Come as you are. Just as I am without one plea, but that thy blood was shed for me, and that thou bid’st me come to thee, O Lamb of God, I come.

In Galatians 4: 12-20 the relationship between the young church and Paul had broken down. They had lost their joy (v 15); they had lost their love. Once they would have torn out their eyes and given them to Paul; now he has apparently become their enemy (v16). They welcomed him because he preached the Gospel to them and that is now what they needed all over again.

Tell me the old, old story of unseen things above; of Jesus and his glory, of Jesus and his love. Tell me the story often for I forget too soon.

And we do. Losing our focus on Jesus means that we lose our joy. We become sour and backslide. We nitpick, especially in other people. We see sinners everywhere, but not sinners saved by grace. Modern Christians seem to think that the Gospel is just about evangelism. It is a story for sinners; we more mature Christians require stronger meat. Nonsense! The Gospel is the Gospel is the Gospel. It needs to be preached to unrepentant sinners. It needs to be preached to young Christians. It needs to be preached to growing Christians. I needs to be preached to mature Christians. It needs to be preached to dying Christians.

Yes and when that world’s glory is dawning on my soul, tell me the old, old story – “Christ Jesus makes thee whole.”

The Galatians had enthusiastically responded to the Judaizers. They were zealous for the Law. It is so easy to believe that now we are saved we must progress to the higher ranks of Christendom. What are the extras we must adopt? The Galatians had become zealots for the Law. It’s fine to be zealous providing the purpose is good (v18). None of us gets worked up over Jewish food laws, I presume, but it is so easy to be zealous over the unimportant. When we were young the zealots were out with prohibitions. You couldn’t be a Christian if you smoked or drank alcohol. Now you may be foolish if you do and there are plenty of health reasons why you should avoid them, but do you really think that God has stopped loving someone because he burns a weed wrapped in paper between his lips? And that is true whatever the weed. God still loves drunks. He sent his son to die for them.

Christians didn’t go to the theatre or the cinema; they didn’t buy a Sunday newspaper; they never went dancing; the television and the radio were silent on a Sunday. I remember being told in a sermon that these long-haired fellows with electric guitars were plugged into Hell. We were zealous for all the wrong things.

Instead we must be zealous for the Gospel. Paul talks about again going through the pains of childbirth for them (v19). It like they have to be born again, again. Whatever our spiritual ills, the remedy is the Gospel.

Every day remember what Jesus Christ has done for you. Begin you prayers with thanksgiving for his love and mercy and his grace. Read the gospel passages regularly. Commit them to memory. Here’s a task that will aid you. Learn John’s gospel off by heart. Sounds impossible? Little children can do it. It doesn’t matter if you fail; the attempt will bless you. It is not a task that will get you into heaven, merely a device to keep the Gospel before your eyes.

If you are a preacher you will no doubt have heard the story of the young man who asked his mentor what he should preach about and received the reply, “Preach about Jesus and preach about 20 minutes.” I wouldn’t worry about the time limit, but otherwise it’s good advice. The Gospel is God’s remedy; never leave it out.

There has been a lot of fuss about the alleged racist remarks by Brian True-May, the producer of the TV series Midsommer Murders. For those who haven't seen it on cable or daytime television, it is set in rural England: Buckinghamshire, Hertfordshire or Oxfordshire, where in these Olde Worlde villages a couple of murders are committed every week in usually quite bizarre ways in order to be solved by the unflappable Chief Inspector Barnaby and his sidekick DS Jones (Jones is the third of his sergeants, the series has been running for so long). In fact the actor, John Nettles, who was once Jersey detective, Bergerac, has just retired to be replaced by Neil Dudgeon, who plays Barnaby's cousin of the same name and rank. Dudgeon has appeared twice before earlier in the series, playing villains.

True-May's great sin was to declare that there has never been a black or brown face in the show, because that would detract from the impression of rural England. Although London is thoroughly multicultural, villages like Great Missenden, where True-May lives, has far less than 0.1% members of ethnic minorities. The villages of Midsommer reflect that 'native Englishness' and True-May wants it preserved. The PC brigade have been all over him, though why they should mind is a mystery to me. There is such a thing as an off switch. I came across this extract from an essay by George Santayana, written in 1922, which expresses quite well this notion of 'Englishness':

Instinctively the Englishman is no missionary, no conqueror. He prefers the country to the town, and home to foreign parts. He is rather glad and relieved if only natives will remain natives and strangers strangers, and at a comfortable distance from himself. Yet outwardly he is most hospitable and accepts almost anybody for the time being; he travels and conquers without a settled design, because he has the instinct of exploration. His adventures are all external; they change him so little that he is not afraid of them. He carries his English weather in his heart wherever he goes, and it becomes a cool spot in the desert, and a steady and sane oracle amongst all the deliriums of mankind. Never since the heroic days of Greece has the world had such a sweet, just, boyish master. It will be a black day for the human race when scientific blackguards, conspirators, churls, and fanatics manage to supplant him.

Although Inspector Barnaby has moved with the times and now drives a Volvo, in the past he has stuck to Rovers and Jaguars and his spirit remains in 1922. This is Agatha Christine without the Art Deco, and what's wrong with that? Over 250 murders in quaint English villages? Hot Fuzz! It's a fantasy! Every bit as much as The Prisoner or Wallace and Grommit.

Wednesday, March 23, 2011

As the end of my chemotherapy gets closer I find that I am just gritting my teeth and hanging on. I am confined to the house because the side effects (especially stomach cramps) persist all the time. Next Tuesday will be the start of my final course. After that the moment of truth when I have my CT scan.

Yesterday I had a visit from Dr Brian Koffman and his wife, who are taking a vacation in Europe. (Regular readers may know of Brian who is a GP from California who has CLL and ITP and has had quite aggressive treatment for them). They had just been in Venice, Rome, Naples and Florence and had had a few days in England with friends. It was a pleasant Spring day and they had a chance to appreciate the sea front here. We had a couple of hours together. We share the experience of being doctors and patients at the same time.

I am afraid that I have been unable to write very much recently. I have put my mind to more mechanical tasks of SUDOKU and model making. I finished a goods depot for my model railway and may make a start today on an engine shed.

The book I am reading at the moment is Voodoo Histories by David Aaronovitch. It is a look at Conspiracy Theories. A strange fact is that the assassinations of JFK, RFK, Martin Luther King and Malcolm X, and the deaths of Marilyn Monroe and Princess Diana are all linked by a complicated conspiracy, but the attempt on the life of Ronald Reagan was just an isolated event by a lone weirdo.

I shall be reviewing the book in the future. In the meantime we have been watching two great world events take place in our living rooms: the disasters in Japan and the uprising in Libya. Obama's response to Libya has much in common with the America First Committee, which opposed FDR's tendency to meddle in foreign wars. Acts passed in the 1930s prevented America giving aid to Abyssinia when invaded by fascist Italy to the republican government of Spain when Franco's fascists rose up against them, to China when Japan marched into Manchuria, and allowed Hitler to occupy the Ruhr, to annexe Austria and march into the Sudetenland unopposed. For a superpower whether or not to act as the world's policeman is always a dilemma. It is probably true to say that it should always act in its own interest, but that does sometimes require prophylactic action. Perhaps Pearl Harbor would have been forestalled if action had been taken over Manchuria. Perhaps World War II would have been prevented had America joined the League of Nations. Perhaps the current mess in the Middle East would have been prevented had Eisenhower supported Britain, France and Israel in 1956?

What has happened in Japan is, of course, awful. One of the spin-offs has been a hardening of opinion against nuclear power. This knee-jerk reaction ought to fade away on mature reflection. Where else is sufficient energy going to come from? Lessons should be learned, however, principally that we shouldn't build such power stations close to where they can be damaged by earthquakes and tsunamis.

Sunday, March 20, 2011

I don't know how you are about women in symphony orchestras. I suppose it's alright for them to be violinists of flautists, but when it comes to the big brass instruments like trombones... well it's a fact that women have smaller lungs than men. Can you envision a woman playing a trombone of a tuba?

That is exactly how German orchestra bosses felt in the 1980s. Then they started holding auditions behind screens and lo and behold, some of the best trombone players were women. I came upon this story in Malcolm Gladwell's book, Blink, which is about the power that our subconscious has over us.

This power is made use of in speed dating, where couple have 5 minutes to meet and greet and then move on to the next victim. It's all about first impressions; couples either hit it off instantly or they do not. Mature reflection might mean it's a disastrous match, but it's surprising how strong that first impression can be.

Most of us would agree that we are not facially prejudiced. Mature reflection tells us that skin color has nothing to do with ability of how pleasant a person is. But tests developed to test our subconscious first impressions indicate that 80% of us are prejudiced and that includes 58% of black people who also prefer white! It may be that our language - black marks, black-hearted, blackguards, dark motives - has conditioned us, but there is no doubt that this instantaneous reaction is there.

You can see it in cop-shootings. A young black American is far more likely to be inadvertently shot by police in America than a young white man. In situations we think of as dangerous we are far more likely to rely on our first impressions than our mature reflections.

You can see it in voter's choices too. Warren Harding is universally regarded as the worst President ever in America. Yet he was tall, handsome, with wonderful hair and a marvelously reassuring voice. He was remarkably handled by his chief of staff and was easily elected. Yet the signs were there. He arranged to be absent for Senatorial debates on the two big issues of his day, women's suffrage and prohibition. But the first impression he gave was marvelous. In the UK, we might say the same about Tony Blair. It is a fact that we tend to elect tall men with regular features and a pleasant manner. We were very lucky to get the short fat and bald Winston Churchill.

Recognizing that we have this subconscious mind making decisions that may be at odds with our mature reflections which should be listen to? Freud had an answer: he said that for simple decisions we should lay out the pros and cons and think about our choice, but that complex decisions were too complicated to think about and that we should rely on our subconscious. You are more likely to spot an Art fraud or laugh at a joke on first impressions than on detailed examination

Wednesday, March 16, 2011

The chemotherapy gets more difficult to bear. Side effects continued even to the morning of my current and penultimate course which began yesterday. Last night, because of the dexamethasone pre-med, I got only 2 hours sleep. My birthday on Saturday was not very enjoyable because I felt so unwell and quite depressed. Still, thanks for all the e-cards and well wishes from such a large number of people. They, at least, were appreciated.

At last Spring has sprung which is a cue for a song:

Spring is sprung the grass is rizzOi wonder where them boidies is?They say the boids is on the wing but that's absoidFrom what I hoid, the wing is always on the boid.

We have the cherry blossom out at last and fat wood pigeons eating it. Forsythia is full out, bright yellow in the front of the house with several patches of daffodils echoing the color. At the back the first of the camellias shines bright scarlet in the sunshine; the others are in heavy bud as are the magnolias. I counted 30 hyacinths in bloom; these are pot plants that we have placed outside in the flower bed. Violets and periwinkle are also flowering and the first of the grape hyacinths. A laurel has been flowering with dark brown blooms for most of the winter and so has the viburnum, though white/pink, not brown. A few cyclamen remain but most have finished flowering. Quite a rarity is the Dorset snowflake which resembles a snowdrop but is much taller with stems about 14 inches high.

Nice to see Manchester United reaching the last eight of the Champions League, though two more players were lost to injury. At least they had Nani and Valencia back. Afer fielding a side against Arsenal with 5 full backs last week they are in danger of having to play with only three defenders next game. They join Spurs and possibly Chelsea who carry a two-goal lead into tonight's match against FC Copenhagen.

We watched East of Eden last night. Well acted by Raymond Massey, but the Oscar nominations went to Elia Kazan, James Dean, and the adaptor of John Steinbeck's novel, Paul Osborn. The Oscar for best supporting actress went to Jo Van Fleet playing the estranged wife and mother. She was better known as a stage actress but she did appear in The Rose Tattoo, I'll Cry Tomorrow (both 1955), The King and Four Queens (1956), Gunfight at the O.K. Corral (1957), and Cool Hand Luke (1967).

I have finished reading the last but one of the Robert Jordan series The Wheel of Time. The last volume will be published in November. That gives me something to aim for.

We have decided to defer selling our house. With summer coming we intend to take an extended holiday. The stress of moving is the last thing I want. We have had very few family holidays, my work has always been so all-consuming. This year will be different.

Friday, March 11, 2011

I watched Inception last night. This film by Christopher Nolan has attracted a lot of attention. It had the same ideas and CGI techniques as The Matrix and having seen one of these things you can guess what is happening. The film is a fine romp, but give me The Heiress any day.

Because CT scanning is the only way to follow what is happening in lymphoma, oncologists assume that it should be done in CLL. Nothing could be further from the truth. In the issue of Blood of February 10th a paper from the German group looked at the value of CT scanning in a dataset that included the CLL4, CLL5 and CLL8 phase 3 clinical trials. This included 1372 patients. In these trials progression was an end point. There were 481 events that were counted as progressive disease. Of these 372 (77%) were picked up by the blood count or by symptoms and physical examination. CT scan picked up 44 progressions (9%) and ultrasound 29 cases (6%). A decision to retreat the patient was made on the basis of CT scan on only 2 patients out of 176. CT scanning had an impact on the prognosis of patients in CR after chemotherapy but not after immunochemotherapy.

They conclude that the methods used for staging and follow-up of patients with CLL should be blood counts and clinical history and examination, as recommended in the IWCLL Guidelines. There are specific clinical situations where CT scanning might be useful. These include when treatment with alemtuzumab is contemplated; glands >5cm in diameter predict a poor response. Another reason might be when FISH shows an 11q deletion, especially in younger patients and yet another indication would be in preparation for a stem cell allograft.

Thursday, March 10, 2011

I am just getting over my 10th (19th overall) course of chemotherapy. Only two to go! By now I am used to the side effects. By the end of the 46 hour infusion I am exhausted and just want to sleep and this persists until the end of day 5. After that I begin to get a little more lively, though I am still easily tired, having to rest after any exertion (including eating). From then on I get abdominal symptoms of bloating, wind and colicky pains. Today is day 10 and I am beginning to feel better, though still bloated. By day 14 I shall feel almost normal and then I start again. I still have the remnants of a cold hanging on which intensifies the symptoms.

Saturday is my birthday; I shall be 68. When I got the diagnosis I didn't expect to live this long. Now I have hopes of making my three score years and ten.

The highest white count that I have seen in CLL is 800,000/cu mm though Tom Kipps told me of a patient with 1,400,000/cu mm. The odd thing is that neither of us has ever seen leukostasis in CLL. This is the condition, often seen in myeloid malignancies where sludging of white cells in blood vessels cuts off the circulation to a particular organ. Commonly, the eye or the brain is involved, causing blindness or stroke, but occasionally it is the penis, leading to priapism. It is one of the reasons for using leukapheresis as a treatment.

Can it occur in CLL? There are very few case reports dealing with chronic lymphocytic leukemia (CLL) and hyperleukocytosis that have been reported in the medical literature. This case was described in 2002 in Leukemia Lymphoma. Cukerman et al described a 73-year-old woman who presented with newly diagnosed CLL, leukostasis, and a white count of 2,000,000/cu mm, affecting the respiratory and nervous system. She responded to leukapheresis followed by chemotherapy. In addition, she also had deep vein thrombosis (DVT).

Deep venous thrombosis usually occurs in the leg and is dangerous because it is the commonest source of pulmonary emboli and these may be fatal. If the thrombosis is confined to the calf it seldom causes more than local trouble, but if it extends above the knee, anticoagulation is necessary to prevent a piece of thrombus breaking off and traveling via the heart to the lungs. The other problem that can arise following venous thrombosis is swelling of the legs. Although veins heal up and become patent again, they lose the valvular mechanism that allows us to sustain a tall column of blood without fluid spilling through the capillaries into the tissue. This is why it is sensible to wear a support stocking for at least a year after a DVT and possibly permanently.

Are DVTs commoner in CLL than in the general population? A paper has just appeared in the journal I edit (Leukemia Research) which looks at this question. (Annika M. Whittle,David J. Allsup and James R. Bailey Chronic lymphocytic leukaemia is a risk factor for venous thromboembolism Leukemia Research 35:419-421 March 2011.)

The reported incidence for venous thromboembolism (VTE) in the general population is around 0.15–0.2% per patient year in adults, with two- to threefold higher rates in the over 60-year olds. In an unselected lymphoma population the incidence is much higher at 6.4%

Whittle et al have 268 patients with CLL on their books with a median duration of follow up of 5.4 years. They act as a referral center in north-east England for a population of 1.1 million. In a retrospective survey they identified from hospital records all cases of VTE identified both among CLL patients and others. There were 15 cases of VTE among 14 patients (5.22%). The incidence per patient year of follow up was 1.45%. Many of the patients had other risk factors for VTE including obesity (2) immobility (3), acute infection (3), a recent airplane flight (1) and enlarged lymph nodes in an appropriate area (2). 7 of the VTE events occurred in Binet stage C patients who represented a minority of patients. One patient probably had thrombophilia since she had had a history of DVTs and pulmonary emboli throughout her life before she developed CLL. None of the patients had a formal thrombophilia screen. All bar 2 of the patients were over-60.

The annual incidence of VTE in this group of patients was 3-10 times higher than that of the general population but only about a quarter of that of the lymphoma population. It was not related to the height of the white count but was associated with more advanced disease. The incidence may be biased by over-observation since CLL patients are more iintensely observed than the general population, and DVTs are often missed in general practice, especially in older people.

Doctors should be aware that CLL patients are at greater risk for DVT than the general population, but at 1.45% a year they are not going to see many cases.

We watched Scorcese's Shutter Island last night. It was, I suppose, what is known as a psychological thriller. I have got into the irritating habit of saying aloud what I think will be the next words by a given character, as if I were the writer. This film allowed you to do this, which, I guess, means that the plot line was fairly obvious. I often spend some time digesting a movie after I go to bed. Not this time though. Some of the images were a bit gross and it was not a frightener except for those who don't like rats. Somehow so many dream sequences took the terror away.

One of the great mysteries about CLL is what the cell of origin is. Based on its CD5 positivity it was originally thought to be derived from a follicular mantle cell, which was why everybody was so surprised to find that so many cases had mutated IGHV genes. Then there were those who thought it derived from the equivalent of the mouse B1 cell. B1 cells are self-renewing CD5+ B cells that mainly live in the peritoneal cavities of mice and produce 'polyreactive' or 'natural' antibodies. They respond to T-independent antigens but rarely accumulate somatic mutations or switch Ig classes to IgA or IgG.

However, no human equivalent of the B1 cell has so far been recognized; although CD5+ human B cells do exist in the circulation, follicular mantles and possibly the omentum, they do not produce 'polyreactive' Ig, they do not mature into plasma cells with appropriate stimulation and they do not show stereotypy.

When I first discovered that patients with mutated and unmutated IGHV genes had clinically different CLL, I postulated that there were two types of CLL derived from different cell types with a different history of exposure to antigen and a different pathway of differentiation, but this was clearly shown not to be the case by gene expression profiling. The difference in gene expression between U-CLL and M-CLL amounted to only a few hundred genes, whereas the difference between CLL as a whole and either memory of naive amounts to thousands.

To reconcile the difference between the BCR implications and the gene profiling data, some experts proposed an origin in the follicular marginal zone (MZ). The figure illustrates a splenic follicle. The germinal center is surrounded by the darker follicular mantle which itself is surrounded by the marginal zone. MZ cells exist in the outermost part of the white pulp of the spleen, in tonsilar subepithelial areas, in the dome regions of Peyer's patches in the gut, and the subcapsular regions of lymph nodes.

MZ B cells have bright surface IgM and dim surface IgD and respond to T-independent stimuli. Their IGHV genes can be mutated or unmutated varying according to anatomical site, though they can reach 70% mutated in the spleen. However, MZ cells are CD5-, CD23-, CD22+; at odds with CLL cells. It would have to be postulated that CLL cells are frozen in a semi-activated state and that the CD5+, CD23+ CD22- phenotype is a sign of activation, not lineage.

In the issue of Blood of 10 February 2011 p 1781, Chiorazzi and Ferrarini publish an article taking a look at this hypothesis in the light of recent research. Among new facts to emerge is that the surface Ig of, particularly U-CLL, cells is a polyspecific antibody often directed against antigens revealed during apoptosis (e.g. non-muscle myosin heavy chain IIA).

Some cases of CLL share BCRs of remarkably similar DNA sequence. These 'stereotyped' CLL comprise about 30% of all CLLs and the HCDR3s are often coded by identical gene sequences, though identical amino acid sequences may be found even though the genes are different. Stereotypy is mostly among U-CLL giving rise to the possibility that there are two types of CLL: stereotyped and non-stereotyped. Possibly the stereotyped CLLs derive from a population of B cells whose function is the clearing-up of the mess after programmed cell death.

When we originally had this debate about cells with unmutated IGHV genes resembling memory cells but not fitting the definition, at a meeting I coined the phrase 'antigen experienced cells', which has passed into the vernacular without acknowledgement. Next time I will write down my 'bon mots' rather than spilling them into the air. Memory cells are defined by their ability to recognize an invader more successfully the second time around, having undergone molecular alterations to facilitate this. For cells programmed to recognize inflammatory debris - with polyspecific antibodies and anti-apoptotic products - alteration of the molecular state of the BCR is perhaps unnecessary, memory being achieved by clonal expansion and perhaps epigenetic changes. U-CLL, particularly stereotyped U-CLL might derive from a cell with an 'antigen experience' like this.

We are beginning to recognize how the leukemic process is imposed on whatever cell is the CLL progenitor. We have seen that many people have a small CLL-like clone of cells that gets more easily detectable as the person ages and that such a clone is more commonly found in people with a relative who has CLL. We know that not all such cases of monoclonal B-cell lymphocytosis (MBL) are CLL-like; some resemble marginal cells. We also know that it is relatively rare for such proliferations to turn into frank CLL. We have seen that there is a distinction between an MBL population of >1000/ cu mm and those with a smaller population than this in that those with a smaller population do not have the same biased use of VH genes and lack the stereotypy seen in CLL. They are also much less likely to transform to CLL. Those with the large population transform at a rate of about 1% a year.

We have recognized certain genetic lesions to be common in both sporadic and familial cases of CLL. Most common is a disorder of 13q14 which takes out the function of the LEU2/miR15-a/miR16-1 complex; effectively a tumor-suppressor gene. This lesion does not seem to be a feature of low count MBL but is present in high count MBL. One case of familial CLL had a mutation of miR16-1 in the germline and the same lesion is found in the NZB mouse germline which develop a CLL-like illness in old age. In a mouse model in which the LEU2/miR15-a/miR16-1 complex has been deleted a CLL-like disease develops. Other miR genes may be involved in other features of the disease. For example, miR29a/29b and miR181a/181b are involved in modulating expression of TCL1 which activates pathways involved in apoptosis and proliferation. These deletions are not infrequent in CLL and transgenic mice that over-express TCL1 develop a disease that resembles U-CLL.

Although we do not know what gene may be involved in trisomy 12 CLL we do know that the CLL associated with trisomy 12 is rather different from other forms in that the morphology is often atypical with more prolymphocytes than normal and the markers tend to be rather different with slightly more dense surface Ig, CD79b and CD20, and greater tendency to express FMC7 and CD22. They are likely to develop other trisomies (especially of chromosomes 16, 18 and 19). However, the patients behave quite normally clinically.

There is evidence that epigenetic mechanisms may also be involved. A single kindred was found to carry a mutation that silenced the DAPK1 gene. Although no other familial cases had this mutation a single sporadic case was found in a different far away country. However this gene is frequently methylated in both sporadic and familial cases of CLL.

It has become clear that the development of CLL develops stepwise. Although virtually all cases of CLL go through an MBL step, very few cases of MBL actually progress. Familial cases may be mutated and unmutated in the same kindred and have a higher incidence of other types of lymphoma.

In the search for a cell of origin for CLL we are no nearer an answer than we were 20 years ago. We cannot find a human B1 equivalent. We recognize the expression of cell markers as fluid, more likely to represent activation that lineage. We are not surprised by clinical differences, which may represent the summation of acquired genetic lesions. The U-CLL/M-CLL split may have several explanations. Quite apart from it representing an origin at a different stage of differentiation, it may simply indicate an acquired defect of spontaneous mutation. The high levels of AID in U-CLL might indicate this.

Saturday, March 05, 2011

I have now had a chance to study the paper from the Mayo Clinic that found an association between low levels of vitamin D and poor prognosis in CLL. Obvious to all is the possibility that vitamin D supplements might improve the lot of CLL patients. Do we have enough information to recommend this?

390 patients with CLL (diagnosed by the 1996 guidelines of >5000/cu mm of lymphocytes in the blood) were observed. The following prognostic factors were measured at diagnosis: Rai stage, CD38, ZAP-70, IGHV mutations, CD49d, and FISH for del 13q, +12, del 11q and del 17p. All had their 25(OH) vitamin D levels measured in their serum. This was the discovery cohort. A confirmation cohort comprised 159 other untreated patients.

Vitamin D insufficiency was defined as <25 ng/mL. 119/390 (30.5%) patients in the discovery cohort were found to be vitamin D insufficient. Insufficiency had no relationship with any of the prognostic factors measured, or to the time of the year that it was measured. Time to treatment (TTT) and overall survival (OS) were shorter in the vitamin D insufficient cases.

In the confirmation cohort 39.9% were vitamin D insufficient. Again this did not correlate with other prognostic factors, except in the case of CD38 with which there was a statistically significant correlation. Again both TTT and OS were shorter in the vitamin D insufficient group. On multivariate analysis vitamin D insufficiency was an independent prognostic factor for TTT but not for OS.

Interestingly, for patients with mutated VH genes or with negative ZAP-70, having a low vitamin D level had no effect on overall survival, but it was associated with a poorer outcome for ZAP-70 positive patients and those with unmutated VH genes. It had a deleterious effect on patients with standard risk FISH (del 13q, normal karyotype and 12+) but did not influence those with poor risk FISH (del 1q and del 17p).

It is important to remember that association is not the same as causation. Even if causation were proved one would not know which caused which. Does having a poor prognosis CLL make your vitamin D level go down or vice versa? It helps if you want to suggest causation to have a plausible mechanism to account for it. The vitamin D receptor is highly expressed on B lymphocytes and it is known that vitamin D derivatives can induce caspase 3 and caspase 9-dependent apoptosis in the test tube. A number of biochemical pathways within B cells are influenced by vitamin D analogs including the MAPK pathway and the ERK pathway.

Low serum vitamin D levels have been found in association with an increased incidence of colorectal, breast and other cancers and there is one randomized clinical trial which found that supplementing the diet with vitamin D plus calcium reduced the incidence of cancer over that of women given a placebo. Unfortunately there was also a statistically significant reduction in incidence among women who were given calcium without vitamin D.

Thus it should not be assumed that vitamin D supplements will improve the lot of patients with CLL. It may do so but it should not be assumed. As a warning we should remember that two observational studies suggested that low levels of vitamin A (in the form of beta-carotene) were associated with a higher incidence of lung cancer. Unfortunately dietary supplementation made no difference to the incidence.

A clinical trial of vitamin D supplementation in CLL is clearly warranted, but at the moment there is no need for everybody with ‘insufficient’ levels to visit the health food shop.

Thursday, March 03, 2011

Lat night we watched The Heiress, a reworking of the Henry James novella Washington Square, starring Olivia De Havilland, Ralph Richardson and Mongomery Clift.

The story is well known. A rather plain and uninteresting girl is a disappointment to her father, a successful and accomplished doctor. She is unexpectedly courted by a handsome and well-mannered young man who proposes marriage. The doctor, suspecting a fortune hunter, threatens to disinherit her. Despite this they plan to elope, but the young man with only 10,000 dollars a year to collect rather than the 30,000 he was expecting does not turn up. She blames her father and he dies with their differences unresolved. Years later the young man turns up and tries it on again but she exacts her revenge on him.

A comment on the father's actions: he was more concerned with doing what was right than with doing what was good.

The 1949 film is excellent. It was directed with terrific skill by Wiliam Wyler and Olivia De Havilland won her second Oscar for the part. Richardson was also nominated and it is hard to see how he did not win (Broderick Crawford won for "All the King's Men.")

Aaron Copeland won an Oscar for the score and the song Plaisir d'Amour was featured. The lyrics sum up the theme of the film:

The UK government has raised the price of alcohol. They have forbidden supermarkets from sell it as such a loss-leader that it costs less than the combined VAT and excise duty of 34 cents a unit for beer and slightly more for spirits.

The burden of alcoholism is such that it contributes to up to 40,000 deaths a year in the UK - nearly one in ten - and to 863,000 hospital admissions a day. The price rise will contribute nothing of benefit to that.

Just as with tobacco, price is the biggest influence on consumption. With the current recession people are drinking slightly less, but there is a big way to go, with Scotland being one of the drunkest nations on the planet (all those dark winters).

The Royal College of Physicians has recommended that price rise to around 75 cents a unit, which it is estimated would result in 3393 fewer deaths, 97,900 fewer hospital admissions, 45,800 fewer crimes, 296,900 fewer days of work, and a total saving to the UK economy of $22.5 billion over 10 years.

Heavy drinkers buy 15 times more alcohol than moderate drinkers, spend 10 times as much and pay 40% less per liter of pure alcohol by buying cheaper versions. This increase would therefore target the heavy drinker who is most vulnerable and would actually benefit the average shopper since the losses made on alcohol by the supermarkets and recompensed by putting up the prices of everything else.

Commentators have suggested that successive governments have listened too much to the alcohol industry and too little to health professionals.

WE know that TP53 problems are about the worst you can have with CLL, but we also know that 17p deletion is very rare in newly diagnosed patients. But what about TP53 mutations which seem to be as important?

The Swedish group run by Richard Rosenquist has looked at this.(Leuk Res 2011; 35:272) Among 268 newly diagnosed patients there were 10 who had del 17p at presentation (3.7%). Of these 7 also had TP53 mutations. 8/10 had unmutated VH genes and 5/7 with both TP53 genes affected were Binet stage B at presentation. There were only 3 (1,1%) patients with TP53 mutations and no del 17p; 2 were Binet stage B, but all three had mutated VH genes. The 3 with del 17p without TP53 mutations were all Binet stage A, but 2 had unmutated VH genes.

Even among this group with an early diagnosis and no previous treatment, time to treatment and overall survival was extremely impaired in patients whose TP53 lesion occurred on both chromosomes. Although the numbers were two small to be examined statistically among the 6 patients with only one chromosome involved three did badly. One with del 17p was treated after 5 days and died 55 months later and another with this lesion received treatment after 4 months and died 4 years after diagnosis. The other (with mutated VH genes) is alive and untreated after 9 years. Of the 3 with only mutated TP53, one was treated at 5 months and died 66 months later, while the other two were alive and well at 118 and 121 months although one was treated at 24 months.

Wednesday, March 02, 2011

We watched Toy Story 3 last night. Tom Hanks got his break in Splash out of hundreds who read for the part. As in Blink this was a first impression decision by the producer Brian Grazer. It was because Hanks was instantly likable. He wasn't the funniest or the best looking actor interviewed, but he was able to do 'mean' and you forgave him, even if he made choices you disagreed with, he was still likable. None of us knows him, but we get the impression that he is decent, trustworthy, down to earth and funny. He was made for Woody. Or vice versa.

That being said I didn't think it was as good as Toy Story 2, though probably deserved its Oscar as there was nothing better on show. I think that should preclude a Toy Story 4.

Malpractice insurance is one of the great deterrents to practising medicine in America. A study has shown that three minutes is all it takes. Doctors who get sued spend an average of 15 minutes with their patients while those who are never sued spend an average of 18 minutes.

But it's not the time, but how the time is spent that is the real difference. Doctors who are never sued are more likely to make orienting comments like, "First I'll examine you and then we will talk the problem over" or "I will leave time for your questions" which give patients an idea of what the visit about and when they ought to ask questions. Never-sued doctors engage in 'active listening', saying such things as "Go on, tell me more about that," and they were far more likely to laugh and be funny during the visit. On the other hand there was no difference in the amount of information conveyed.

The interesting thing is that the patients takes in the doctor's attitude within the first few seconds of the consultation. It all boils down to 'Does the doctor respect the patient?' The most corrosive tone of voice that a doctor can adopt is a dominant one. Patients have been known to sue the wrong doctor because they liked one (who had made the mistake) and despised the other (who was entirely innocent). The truth is that all doctors make mistakes but patients are only vindictive if the doctor has not formed a caring relationship with him or her.

I have this information from a book given to me by my older son who was visiting last weekend. Blink by Malcolm Gladwell examines first impressions and hunches. Our unconscious brain makes and early decision that is not available to our conscious thought until minutes, days or even weeks later. Most of us don't trust these first impressions and sometimes we are right not to. The book explores when we should override this censorship.

"It's not fair!" is a common cry of children. "Life isn't fair." is a common adult rejoinder.

John Rawls was an American moral philosopher who died in 2002. Much of his thinking has been adopted by modern Western democracies. Rawls imagines that were we to design a society from scratch, we would build in a social contract. He considers that the basis of justice is to restore some of the fairness that nature and previous experience have omitted.

Rawls begins with the principle of liberty; establishing equal basic liberties for all citizens. 'Basic' liberty entails the freedoms of conscience, association, and expression as well as democratic rights; Rawls also includes a right to own personal property.

Rawls argues for a second principle of equality. To guarantee that liberties represent meaningful options for all in society he proposes distributive justice. Formal guarantees of political voice and freedom of assembly are of little real value to the desperately poor and marginalized in society. However, demanding that everyone have exactly the same effective opportunities in life would almost certainly offend the very liberties that are supposedly being equalized. Nevertheless, for our liberties to matter, wherever one ends up in society, one wants life to be worth living, with enough effective freedom to pursue personal goals. Thus Rawls affirms a two-part second principle comprising Fair Equality of Opportunity and the famous (and controversial) difference principle. This second principle ensures that those with comparable talents and motivation face roughly similar life chances and that inequalities in society work to the benefit of the least advantaged.

In order to construct society as a thought experiment, Rawls proposed a 'veil of ignorance'. In other words he proposed that philosophers in designing society should not know where they would end up. The should assume that they might end up at the bottom and be as content with their design

One early way of ordering society was the feudal. Aristocrats, my virtue of birth are as a gift from the king could do pretty well what they liked while the peasants did what they were told. Very few societies operate on such principles today and most that do are almost universally condemned. A semblance of this former state exists where there are still monarchies, but in real life these are really an example of pageantry and a device to stop politicians getting too powerful.

A second way was the libertarian, exemplified by the American wild west and in a modified way still preferred by some of my readers. The problem with this is that upbringing and background still confers an unfair advantage to those who are the winners, even if the law is sufficient and enforced sufficiently to deter crooks and confidence tricksters.

Many espouse a meritocracy. But even here wealth and schooling confer an unfair advantage on some. As someone who rose to the top without any of these advantages, I remember resenting those who advanced more rapidly than I by virtue of their public school accents, straight teeth and Oxbridge contacts. My children had their teeth straightened, their accents adjusted to RP and at least one of them went to Oxford. These things can be corrected of course. Orthodontics is now available to all via the NHS, pains are being taken to make allowances at Oxbridge admissions for people without the benefit of a private education and resistance to regional accents is fading. More could be done to level the playing field, though it is hard to stop rich parents buying privilege for their children.

I have always felt that credit should be given to those who by dint of hard work and application made their way to the top except that I have not made sufficient allowance for the birth order effect. Seventy per cent of Harvard students are the first-born in their families. I was the first-born in mine. Although you might credit me for raising myself above my roots, there can be no merit in being born first.

Rawls therefore proposes a fourth solution: a society based on meritocracy where social manipulation aids the least gifted - social housing, nursery education, free health care etc with higher taxes for the rich. The problem with this is that the rich will just move elsewhere, where the taxes are lower. The trick is to make the standard of living such that even though the taxes are high they are better off staying put. Then you have the problem of immigration, much of which will be illegal.

The trouble with life is it's just not fair. But that is also its challenge.

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About Me

Born in Worcester, England 1943; school at Farnborough, Hampshire 1954-62; University 1962-7 and junior doctor posts 1967-74 in Bristol; Consultant Haematologist Bournemouth 1974-2003; Professor of Immunohaematology Southampton 1986 to present. Honorary Consultant Haematologist Kings College Hospital, London, 2004-present. After 5 years of working part time researching, writing, reviewing, editing, speaking, sitting on committees, advising, answering questions and thinking, I now think of myself as fully retired apart from my role as Editor in Chief of the medical journal Leukemia Research. I was awarded the Binet-Rai medal for outstanding research in CLL in 2002 and this has been my most sucessful area of research, but I have also made important contributions in the fields of apheresis, stem cell transplantation, myeloma, myelodysplastic syndrome, antibody therapy, cytokine therapy and DNA vaccines. I was once mascot for Aldershot Town Football. Club. Married to Diane for 44 years. Four children, Karen, Richard, Angela and David.